Project Summary Glucose is the primary fuel used by the brain. While alternative energy substrates can transiently sustain the brain?s needs during hypoglycemic episodes, glucose-sensing neurons within the brain nonetheless respond to diminishing energy supplies by altering their electrical behavior. This cellular response often has significant ramifications for the electrical activity patterns produced by neural networks assembled from those neurons. In this project, we aim to identify the mechanisms responsible for this heightened glucosensitivity in a brain structure known as the thalamus, and to determine how these mechanisms promote seizures. Our multifaceted approach utilizes calcium imaging and electrophysiological techniques to test the general hypothesis that glucose directly modulates neural circuits in the thalamus to exacerbate seizures. Using our preliminary data as a launching point, we will begin by carrying out experiments designed to (1) directly measure glucose levels in the thalamus while concomitantly recording seizure activity, and (2) selectively modulate glucose handling in the thalamus and measure impact on seizures. Additionally, measurements of neuronal activity in the thalamus during control and fasted conditions will be achieved directly through in vivo calcium imaging approaches as well as by blood oxygenation level dependent (BOLD) signals acquired during functional MRI studies. Collectively, these experiments will establish the thalamus, a critical seizure-generating node in the brain, as a glucosensitive structure. In conjunction with our glucose and seizure measurements, we will utilize electrophysiological and imaging techniques in acute brain slice preparations to directly measure the sensitivity of thalamic neurons to glucose. These experiments will be performed both at the cellular and circuit level. The former is achieved by conventional patch clamp recordings, while the latter is achieved in the context of slice models of thalamic seizures; our lab has extensive experience with both. By performing these reductionist experiments, we aim to pinpoint mechanisms within the thalamic circuit that are particularly vulnerable to hypoglycemic conditions. Finally, in our third aim, we will assess the efficacy of anti-seizure drugs on reducing seizure occurrence in fed and hypoglycemic animals. The motivation for this assessment comes from recent calls to consider that strict glucose monitoring and stabilization in patients may be used as a used adjunct therapy for thalamocortical epilepsy treatment. Our preliminary data agrees with this recommendation, and we have the tools to readily test this possibility.